exclude: true --- class: top left hide-count background-image: url(img/adrian-lange-Wk902ZLaA7M-unsplash_crop.jpg) background-size: cover .move-top5[ .title-text[<span style='font-size:0.9em'>Distances, Trees & Types</span>] .title-subtext[<span style='font-size:0.95em'>Methods for Analyzing High-Dimensional Microbiome Data</span>] ] .callout-url-rightcorner[ .title-nametext[ Brendan J. Kelly, MD, MS Infectious Diseases | Epidemiology | Microbiology University of Pennsylvania 17 June 2024 <!-- 16 June 2024 --> ] ] .footnote-left[<span style='color:#ffffff'>photo: Adrian Lange @unsplash</span>] --- ## Disclosures .pad-left[ - No conflicts of interest. - Research supported by: - NIAID K23 AI121485 - CDC BAA 200-2016-91964 - CDC BAA 200-2016-91937 - CDC BAA 200-2018-02919 - CDC BAA 200-2021-10986 - CDC Prevention Epicenters U54CK000610 - NIAID U19AI174998 ] --- ## Outline: The Microbiome for Epidemiologists .pull-left[ - The problem: **too much** data - the "p > n problem" - Reducing dimensions: - richness, evenness, and diversity - ecological distances (UniFrac) - PCA & PCoA - PERMANOVA (adonis) ] .pull-right[ - Cluster analysis: - supervised vs unsupervised learning - Dirichlet multinomial mixture modeling <img src="img/pptx_img/image25.png" width="80%" style="display: block; margin: auto;" /> ] --- class: top left hide-count background-image: url(img/diana-polekhina-z84ULL2EoKs-unsplash.jpg) background-size: cover ## <span style='color: #093b85;'>Too Much Data</span> .footnote-left[<span style='color: #093b85'>photo: Diana Polekhina @unsplash</span>] --- ## Generating Microbiome Data .pad-left[ - High-density (next-generation, high-throughput) sequencing: - “tag” gene with conserved and variable regions (16S, 18S, ITS) - "shotgun" metagenomics (pool of randomly amplified nucleic acids) - Sequence binning and assignment: - operational taxonomic units (OTUs) based on 97% sequence similarity → taxonomic assignment of OTUs - assemble contiguous metagenomic sequences → taxonomy - unassembled/un-binned reads → taxonomic assignment (e.g., ASVs or SGBs) ] .footnote-left[Callahan BJ _bioArxiv_ 2017] --- ## An Example OTU Table
OTU ID
Specimen_1
Specimen_2
Specimen_3
Specimen_4
Specimen_5
Specimen_6
Specimen_7
Specimen_8
Specimen_9
Specimen_10
1
OTU_1
736
400
989
0
674
380
0
511
24
0
2
OTU_2
826
0
0
697
893
860
460
0
276
0
3
OTU_3
270
564
0
0
252
965
280
348
0
0
4
OTU_4
0
320
571
51
279
937
0
70
668
434
5
OTU_5
989
0
482
658
701
0
674
652
584
704
6..999
1000
OTU_1000
188
724
461
152
469
459
0
61
496
0
--- ## An Example OTU Table: Samples & Variables?
OTU ID
Specimen_1
Specimen_2
Specimen_3
Specimen_4
Specimen_5
Specimen_6
Specimen_7
Specimen_8
Specimen_9
Specimen_10
1
OTU_1
736
400
989
0
674
380
0
511
24
0
2
OTU_2
826
0
0
697
893
860
460
0
276
0
3
OTU_3
270
564
0
0
252
965
280
348
0
0
4
OTU_4
0
320
571
51
279
937
0
70
668
434
5
OTU_5
989
0
482
658
701
0
674
652
584
704
6..999
1000
OTU_1000
188
724
461
152
469
459
0
61
496
0
.pad-left[ - which are the samples and which are the variables? - also note: lots of zeros ] --- ## An Example OTU Table: Samples vs Variables
Specimen ID
OTU_1
OTU_2
OTU_3
OTU_4
OTU_5
OTU_6
OTU_7
OTU_8
OTU_9
OTU_10
OTU_11
OTU_12
OTU_13
OTU_14
OTU_15
OTU_16
OTU_17
OTU_18
OTU_19
OTU_20
OTU_21
OTU_22
OTU_23
OTU_24
OTU_25
OTU_26
OTU_27
OTU_28
OTU_29
OTU_30
OTU_31
OTU_32
OTU_33
OTU_34
OTU_35
OTU_36
OTU_37
OTU_38
OTU_39
OTU_40
OTU_41
OTU_42
OTU_43
OTU_44
OTU_45
OTU_46
OTU_47
OTU_48
OTU_49
OTU_50
OTU_51
OTU_52
OTU_53
OTU_54
OTU_55
OTU_56
OTU_57
OTU_58
OTU_59
OTU_60
OTU_61
OTU_62
OTU_63
OTU_64
OTU_65
OTU_66
OTU_67
OTU_68
OTU_69
OTU_70
OTU_71
OTU_72
OTU_73
OTU_74
OTU_75
OTU_76
OTU_77
OTU_78
OTU_79
OTU_80
OTU_81
OTU_82
OTU_83
OTU_84
OTU_85
OTU_86
OTU_87
OTU_88
OTU_89
OTU_90
OTU_91
OTU_92
OTU_93
OTU_94
OTU_95
OTU_96
OTU_97
OTU_98
OTU_99
OTU_100
OTU_101
OTU_102
OTU_103
OTU_104
OTU_105
OTU_106
OTU_107
OTU_108
OTU_109
OTU_110
OTU_111
OTU_112
OTU_113
OTU_114
OTU_115
OTU_116
OTU_117
OTU_118
OTU_119
OTU_120
OTU_121
OTU_122
OTU_123
OTU_124
OTU_125
OTU_126
OTU_127
OTU_128
OTU_129
OTU_130
OTU_131
OTU_132
OTU_133
OTU_134
OTU_135
OTU_136
OTU_137
OTU_138
OTU_139
OTU_140
OTU_141
OTU_142
OTU_143
OTU_144
OTU_145
OTU_146
OTU_147
OTU_148
OTU_149
OTU_150
OTU_151
OTU_152
OTU_153
OTU_154
OTU_155
OTU_156
OTU_157
OTU_158
OTU_159
OTU_160
OTU_161
OTU_162
OTU_163
OTU_164
OTU_165
OTU_166
OTU_167
OTU_168
OTU_169
OTU_170
OTU_171
OTU_172
OTU_173
OTU_174
OTU_175
OTU_176
OTU_177
OTU_178
OTU_179
OTU_180
OTU_181
OTU_182
OTU_183
OTU_184
OTU_185
OTU_186
OTU_187
OTU_188
OTU_189
OTU_190
OTU_191
OTU_192
OTU_193
OTU_194
OTU_195
OTU_196
OTU_197
OTU_198
OTU_199
OTU_200
OTU_201
OTU_202
OTU_203
OTU_204
OTU_205
OTU_206
OTU_207
OTU_208
OTU_209
OTU_210
OTU_211
OTU_212
OTU_213
OTU_214
OTU_215
OTU_216
OTU_217
OTU_218
OTU_219
OTU_220
OTU_221
OTU_222
OTU_223
OTU_224
OTU_225
OTU_226
OTU_227
OTU_228
OTU_229
OTU_230
OTU_231
OTU_232
OTU_233
OTU_234
OTU_235
OTU_236
OTU_237
OTU_238
OTU_239
OTU_240
OTU_241
OTU_242
OTU_243
OTU_244
OTU_245
OTU_246
OTU_247
OTU_248
OTU_249
OTU_250
OTU_251
OTU_252
OTU_253
OTU_254
OTU_255
OTU_256
OTU_257
OTU_258
OTU_259
OTU_260
OTU_261
OTU_262
OTU_263
OTU_264
OTU_265
OTU_266
OTU_267
OTU_268
OTU_269
OTU_270
OTU_271
OTU_272
OTU_273
OTU_274
OTU_275
OTU_276
OTU_277
OTU_278
OTU_279
OTU_280
OTU_281
OTU_282
OTU_283
OTU_284
OTU_285
OTU_286
OTU_287
OTU_288
OTU_289
OTU_290
OTU_291
OTU_292
OTU_293
OTU_294
OTU_295
OTU_296
OTU_297
OTU_298
OTU_299
OTU_300
OTU_301
OTU_302
OTU_303
OTU_304
OTU_305
OTU_306
OTU_307
OTU_308
OTU_309
OTU_310
OTU_311
OTU_312
OTU_313
OTU_314
OTU_315
OTU_316
OTU_317
OTU_318
OTU_319
OTU_320
OTU_321
OTU_322
OTU_323
OTU_324
OTU_325
OTU_326
OTU_327
OTU_328
OTU_329
OTU_330
OTU_331
OTU_332
OTU_333
OTU_334
OTU_335
OTU_336
OTU_337
OTU_338
OTU_339
OTU_340
OTU_341
OTU_342
OTU_343
OTU_344
OTU_345
OTU_346
OTU_347
OTU_348
OTU_349
OTU_350
OTU_351
OTU_352
OTU_353
OTU_354
OTU_355
OTU_356
OTU_357
OTU_358
OTU_359
OTU_360
OTU_361
OTU_362
OTU_363
OTU_364
OTU_365
OTU_366
OTU_367
OTU_368
OTU_369
OTU_370
OTU_371
OTU_372
OTU_373
OTU_374
OTU_375
OTU_376
OTU_377
OTU_378
OTU_379
OTU_380
OTU_381
OTU_382
OTU_383
OTU_384
OTU_385
OTU_386
OTU_387
OTU_388
OTU_389
OTU_390
OTU_391
OTU_392
OTU_393
OTU_394
OTU_395
OTU_396
OTU_397
OTU_398
OTU_399
OTU_400
OTU_401
OTU_402
OTU_403
OTU_404
OTU_405
OTU_406
OTU_407
OTU_408
OTU_409
OTU_410
OTU_411
OTU_412
OTU_413
OTU_414
OTU_415
OTU_416
OTU_417
OTU_418
OTU_419
OTU_420
OTU_421
OTU_422
OTU_423
OTU_424
OTU_425
OTU_426
OTU_427
OTU_428
OTU_429
OTU_430
OTU_431
OTU_432
OTU_433
OTU_434
OTU_435
OTU_436
OTU_437
OTU_438
OTU_439
OTU_440
OTU_441
OTU_442
OTU_443
OTU_444
OTU_445
OTU_446
OTU_447
OTU_448
OTU_449
OTU_450
OTU_451
OTU_452
OTU_453
OTU_454
OTU_455
OTU_456
OTU_457
OTU_458
OTU_459
OTU_460
OTU_461
OTU_462
OTU_463
OTU_464
OTU_465
OTU_466
OTU_467
OTU_468
OTU_469
OTU_470
OTU_471
OTU_472
OTU_473
OTU_474
OTU_475
OTU_476
OTU_477
OTU_478
OTU_479
OTU_480
OTU_481
OTU_482
OTU_483
OTU_484
OTU_485
OTU_486
OTU_487
OTU_488
OTU_489
OTU_490
OTU_491
OTU_492
OTU_493
OTU_494
OTU_495
OTU_496
OTU_497
OTU_498
OTU_499
OTU_500
OTU_501
OTU_502
OTU_503
OTU_504
OTU_505
OTU_506
OTU_507
OTU_508
OTU_509
OTU_510
OTU_511
OTU_512
OTU_513
OTU_514
OTU_515
OTU_516
OTU_517
OTU_518
OTU_519
OTU_520
OTU_521
OTU_522
OTU_523
OTU_524
OTU_525
OTU_526
OTU_527
OTU_528
OTU_529
OTU_530
OTU_531
OTU_532
OTU_533
OTU_534
OTU_535
OTU_536
OTU_537
OTU_538
OTU_539
OTU_540
OTU_541
OTU_542
OTU_543
OTU_544
OTU_545
OTU_546
OTU_547
OTU_548
OTU_549
OTU_550
OTU_551
OTU_552
OTU_553
OTU_554
OTU_555
OTU_556
OTU_557
OTU_558
OTU_559
OTU_560
OTU_561
OTU_562
OTU_563
OTU_564
OTU_565
OTU_566
OTU_567
OTU_568
OTU_569
OTU_570
OTU_571
OTU_572
OTU_573
OTU_574
OTU_575
OTU_576
OTU_577
OTU_578
OTU_579
OTU_580
OTU_581
OTU_582
OTU_583
OTU_584
OTU_585
OTU_586
OTU_587
OTU_588
OTU_589
OTU_590
OTU_591
OTU_592
OTU_593
OTU_594
OTU_595
OTU_596
OTU_597
OTU_598
OTU_599
OTU_600
OTU_601
OTU_602
OTU_603
OTU_604
OTU_605
OTU_606
OTU_607
OTU_608
OTU_609
OTU_610
OTU_611
OTU_612
OTU_613
OTU_614
OTU_615
OTU_616
OTU_617
OTU_618
OTU_619
OTU_620
OTU_621
OTU_622
OTU_623
OTU_624
OTU_625
OTU_626
OTU_627
OTU_628
OTU_629
OTU_630
OTU_631
OTU_632
OTU_633
OTU_634
OTU_635
OTU_636
OTU_637
OTU_638
OTU_639
OTU_640
OTU_641
OTU_642
OTU_643
OTU_644
OTU_645
OTU_646
OTU_647
OTU_648
OTU_649
OTU_650
OTU_651
OTU_652
OTU_653
OTU_654
OTU_655
OTU_656
OTU_657
OTU_658
OTU_659
OTU_660
OTU_661
OTU_662
OTU_663
OTU_664
OTU_665
OTU_666
OTU_667
OTU_668
OTU_669
OTU_670
OTU_671
OTU_672
OTU_673
OTU_674
OTU_675
OTU_676
OTU_677
OTU_678
OTU_679
OTU_680
OTU_681
OTU_682
OTU_683
OTU_684
OTU_685
OTU_686
OTU_687
OTU_688
OTU_689
OTU_690
OTU_691
OTU_692
OTU_693
OTU_694
OTU_695
OTU_696
OTU_697
OTU_698
OTU_699
OTU_700
OTU_701
OTU_702
OTU_703
OTU_704
OTU_705
OTU_706
OTU_707
OTU_708
OTU_709
OTU_710
OTU_711
OTU_712
OTU_713
OTU_714
OTU_715
OTU_716
OTU_717
OTU_718
OTU_719
OTU_720
OTU_721
OTU_722
OTU_723
OTU_724
OTU_725
OTU_726
OTU_727
OTU_728
OTU_729
OTU_730
OTU_731
OTU_732
OTU_733
OTU_734
OTU_735
OTU_736
OTU_737
OTU_738
OTU_739
OTU_740
OTU_741
OTU_742
OTU_743
OTU_744
OTU_745
OTU_746
OTU_747
OTU_748
OTU_749
OTU_750
OTU_751
OTU_752
OTU_753
OTU_754
OTU_755
OTU_756
OTU_757
OTU_758
OTU_759
OTU_760
OTU_761
OTU_762
OTU_763
OTU_764
OTU_765
OTU_766
OTU_767
OTU_768
OTU_769
OTU_770
OTU_771
OTU_772
OTU_773
OTU_774
OTU_775
OTU_776
OTU_777
OTU_778
OTU_779
OTU_780
OTU_781
OTU_782
OTU_783
OTU_784
OTU_785
OTU_786
OTU_787
OTU_788
OTU_789
OTU_790
OTU_791
OTU_792
OTU_793
OTU_794
OTU_795
OTU_796
OTU_797
OTU_798
OTU_799
OTU_800
OTU_801
OTU_802
OTU_803
OTU_804
OTU_805
OTU_806
OTU_807
OTU_808
OTU_809
OTU_810
OTU_811
OTU_812
OTU_813
OTU_814
OTU_815
OTU_816
OTU_817
OTU_818
OTU_819
OTU_820
OTU_821
OTU_822
OTU_823
OTU_824
OTU_825
OTU_826
OTU_827
OTU_828
OTU_829
OTU_830
OTU_831
OTU_832
OTU_833
OTU_834
OTU_835
OTU_836
OTU_837
OTU_838
OTU_839
OTU_840
OTU_841
OTU_842
OTU_843
OTU_844
OTU_845
OTU_846
OTU_847
OTU_848
OTU_849
OTU_850
OTU_851
OTU_852
OTU_853
OTU_854
OTU_855
OTU_856
OTU_857
OTU_858
OTU_859
OTU_860
OTU_861
OTU_862
OTU_863
OTU_864
OTU_865
OTU_866
OTU_867
OTU_868
OTU_869
OTU_870
OTU_871
OTU_872
OTU_873
OTU_874
OTU_875
OTU_876
OTU_877
OTU_878
OTU_879
OTU_880
OTU_881
OTU_882
OTU_883
OTU_884
OTU_885
OTU_886
OTU_887
OTU_888
OTU_889
OTU_890
OTU_891
OTU_892
OTU_893
OTU_894
OTU_895
OTU_896
OTU_897
OTU_898
OTU_899
OTU_900
OTU_901
OTU_902
OTU_903
OTU_904
OTU_905
OTU_906
OTU_907
OTU_908
OTU_909
OTU_910
OTU_911
OTU_912
OTU_913
OTU_914
OTU_915
OTU_916
OTU_917
OTU_918
OTU_919
OTU_920
OTU_921
OTU_922
OTU_923
OTU_924
OTU_925
OTU_926
OTU_927
OTU_928
OTU_929
OTU_930
OTU_931
OTU_932
OTU_933
OTU_934
OTU_935
OTU_936
OTU_937
OTU_938
OTU_939
OTU_940
OTU_941
OTU_942
OTU_943
OTU_944
OTU_945
OTU_946
OTU_947
OTU_948
OTU_949
OTU_950
OTU_951
OTU_952
OTU_953
OTU_954
OTU_955
OTU_956
OTU_957
OTU_958
OTU_959
OTU_960
OTU_961
OTU_962
OTU_963
OTU_964
OTU_965
OTU_966
OTU_967
OTU_968
OTU_969
OTU_970
OTU_971
OTU_972
OTU_973
OTU_974
OTU_975
OTU_976
OTU_977
OTU_978
OTU_979
OTU_980
OTU_981
OTU_982
OTU_983
OTU_984
OTU_985
OTU_986
OTU_987
OTU_988
OTU_989
OTU_990
OTU_991
OTU_992
OTU_993
OTU_994
OTU_995
OTU_996
OTU_997
OTU_998
OTU_999
OTU_1000
1
Specimen_1
736
826
270
0
989
474
63
636
233
891
0
872
594
0
967
0
0
650
0
714
184
111
0
485
0
970
678
312
0
0
0
0
195
68
836
72
257
339
104
646
943
0
0
270
922
0
98
740
800
0
853
564
0
141
488
186
169
365
0
998
209
668
301
370
585
971
819
0
893
537
266
120
958
0
136
599
599
451
0
0
0
0
467
958
772
0
451
0
57
281
801
331
823
0
670
0
0
193
0
0
305
0
787
919
245
187
517
0
0
82
102
926
179
254
790
743
56
0
0
701
103
973
0
94
261
197
76
0
98
347
151
154
150
632
543
646
993
842
542
377
756
897
797
756
554
0
210
732
344
859
149
736
0
754
167
579
0
0
383
856
0
866
562
323
215
0
752
0
557
0
673
791
176
0
0
576
905
530
0
66
21
877
0
0
0
379
67
0
712
112
0
784
122
859
833
0
164
915
217
320
322
0
0
591
810
784
222
0
0
0
257
0
371
961
262
0
0
431
422
145
790
198
326
737
517
608
785
326
121
0
19
95
0
368
0
17
738
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162
219
637
510
365
260
784
525
628
0
129
888
645
164
874
238
0
792
586
793
464
686
462
0
889
0
0
631
945
663
864
475
636
706
0
0
101
27
646
942
806
370
0
902
378
549
0
0
0
274
505
676
681
0
0
651
0
713
696
825
0
448
963
453
430
0
0
586
796
135
629
601
796
0
624
0
0
321
162
185
826
539
249
940
0
36
430
814
381
792
974
692
333
638
0
489
819
199
447
435
893
798
403
145
350
0
0
547
280
0
57
782
478
772
176
1
0
659
0
733
461
4
Specimen_4
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697
0
51
658
142
0
0
198
61
208
0
676
0
22
619
239
35
323
542
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172
666
519
563
48
673
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115
0
3
77
135
511
909
0
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366
214
0
0
262
133
0
0
25
0
0
782
550
195
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596
355
0
674
879
982
262
757
775
666
517
571
343
380
0
461
0
421
0
255
308
459
929
340
267
318
461
0
604
941
17
36
704
793
0
752
0
565
805
654
408
858
345
903
721
994
804
337
978
786
0
0
736
33
0
0
0
893
778
257
153
456
633
436
162
412
0
976
703
605
0
0
669
314
158
685
373
17
78
0
0
209
583
821
882
809
263
639
93
742
0
529
527
711
969
0
0
647
963
0
0
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451
0
529
0
612
0
89
523
724
970
634
70
0
991
302
63
588
0
799
205
288
148
825
172
0
690
357
936
0
150
821
478
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991
0
0
45
650
825
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0
419
405
480
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226
954
326
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202
783
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393
575
881
2
16
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416
186
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138
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0
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0
932
551
163
426
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0
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251
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243
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150
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730
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112
194
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0
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0
970
886
676
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517
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192
0
535
373
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874
438
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191
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347
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34
374
123
0
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149
0
414
640
217
0
436
65
451
658
268
119
263
0
756
256
0
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0
526
0
278
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801
0
485
136
0
381
184
469
853
0
784
0
616
459
0
131
211
955
262
346
94
0
0
380
740
545
778
455
830
834
680
0
852
0
0
0
723
731
149
0
0
768
439
0
0
669
247
46
603
170
416
776
454
906
39
424
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637
693
705
698
0
606
496
0
0
609
863
819
0
0
814
899
187
226
497
282
952
585
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0
374
554
660
266
770
825
464
0
977
569
184
569
0
937
0
0
242
698
280
965
747
313
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0
0
972
955
0
704
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37
562
61
848
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0
239
0
410
865
679
0
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980
0
164
252
978
964
265
842
0
155
547
0
8
63
457
110
183
301
0
291
0
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146
0
0
152
534
120
0
0
644
0
154
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283
158
0
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148
370
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0
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266
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0
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253
0
462
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153
0
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0
204
519
704
725
82
644
0
472
34
811
711
868
0
710
0
188
461
587
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0
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356
111
580
826
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294
79
0
0
0
218
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419
0
620
305
0
267
733
429
891
315
228
0
425
871
146
0
366
268
858
311
0
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601
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0
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968
204
0
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45
940
328
984
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146
0
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544
714
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0
698
110
907
369
804
336
886
823
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0
0
538
816
324
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399
229
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0
0
170
333
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132
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0
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0
813
332
857
141
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298
957
685
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0
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0
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49
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684
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449
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651
817
862
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0
0
232
289
861
0
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0
279
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0
0
515
60
852
452
801
0
199
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230
234
12
800
600
0
117
771
495
185
264
707
60
548
34
0
880
920
80
344
195
0
842
491
678
706
770
332
87
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204
0
0
931
719
240
259
221
969
986
424
181
641
0
367
129
209
379
85
0
666
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123
74
430
0
354
459
991
97
449
205
0
665
403
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37
0
910
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124
0
284
617
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586
694
132
0
107
710
884
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0
310
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574
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0
646
12
475
985
460
431
33
877
10
0
197
0
359
0
5
864
306
0
452
182
530
16
212
791
0
890
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0
0
107
340
663
525
401
780
300
142
90
911
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522
248
415
553
866
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962
678
872
560
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365
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873
729
66
495
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853
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0
897
650
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283
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703
653
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103
710
194
306
0
0
692
555
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517
773
623
737
380
183
370
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421
257
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120
158
225
552
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113
641
432
449
0
340
6
0
877
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159
619
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960
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0
162
0
354
869
524
430
315
420
964
742
0
901
722
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0
43
0
0
449
125
0
707
643
463
353
559
159
498
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782
417
362
671
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895
893
342
304
0
0
0
153
87
591
0
666
73
607
272
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630
979
308
23
0
0
127
351
167
105
637
828
288
91
500
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491
309
313
1000
868
0
996
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907
53
733
509
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0
168
706
660
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479
527
885
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611
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957
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791
859
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338
375
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117
541
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628
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565
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743
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693
586
903
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173
0
0
0
970
580
626
0
889
152
5
Specimen_5
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893
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279
701
662
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568
949
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390
909
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710
946
947
379
350
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832
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325
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222
90
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10
316
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690
691
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469
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996
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387
396
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362
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820
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710
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537
804
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646
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820
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612
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253
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37
685
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871
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474
666
973
460
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132
844
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633
914
951
998
241
143
459
732
906
430
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519
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0
212
361
502
937
154
0
417
0
8
64
336
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53
998
256
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159
527
203
484
768
337
0
390
161
725
460
791
0
0
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731
117
188
369
624
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0
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879
389
40
328
23
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703
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27
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952
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578
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1
646
987
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651
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125
704
854
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84
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424
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680
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345
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967
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950
83
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695
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420
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422
159
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790
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474
30
689
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233
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532
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707
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124
933
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569
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268
856
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44
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482
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75
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316
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904
708
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648
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175
273
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224
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241
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588
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151
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42
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202
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260
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869
664
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690
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740
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340
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162
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140
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876
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194
83
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466
60
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856
771
281
469
6..9
10
Specimen_10
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30
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549
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521
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1000
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0
409
135
56
225
0
386
331
489
297
650
0
461
810
594
0
86
0
0
0
621
0
337
0
575
926
0
259
723
0
111
520
463
667
0
231
345
516
0
242
709
0
0
956
0
527
288
0
0
931
0
125
278
98
7
461
5
557
798
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482
574
463
358
0
560
984
651
788
203
889
515
951
827
160
226
611
623
365
973
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761
751
4
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118
137
591
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693
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598
872
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481
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944
629
351
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342
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163
458
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729
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584
236
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471
765
399
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0
666
83
642
800
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949
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478
257
173
900
883
470
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873
302
112
591
150
765
795
715
896
0
273
76
251
640
877
0
829
741
69
779
983
379
0
718
326
17
0
0
461
367
952
0
305
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454
428
0
986
465
724
905
16
475
468
910
138
0
0
0
0
0
62
0
0
198
905
144
161
0
0
155
0
0
227
710
61
248
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366
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690
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83
498
693
922
960
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854
496
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342
888
817
610
332
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678
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545
437
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607
489
71
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394
533
111
31
209
904
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0
682
263
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0
863
862
818
525
149
12
200
570
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352
196
347
433
580
680
455
983
613
938
55
601
0
0
0
750
0
376
432
796
754
0
803
897
211
0
112
909
287
31
981
0
383
101
0
422
0
304
0
595
81
2
0
0
725
538
388
638
72
0
288
391
938
878
277
950
878
0
699
140
388
182
216
699
979
744
448
792
177
122
697
757
167
958
750
660
0
683
0
987
510
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765
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873
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240
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432
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182
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80
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600
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779
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851
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56
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962
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915
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875
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.pad-left[ - OTUs are really *columns* (i.e., variables) & specimens *rows* (i.e., observations) - 10 rows & 1000 columns → p >> n → overfitting risk ] --- class: top left hide-count background-image: url(img/michael-48yI_ZyzuLo-unsplash.jpg) background-size: cover ## <span style='color: black;'>Reducing Dimensions</span> .footnote-right[<span style='color: white'>photo: Michael @unsplash</span>] --- ## High-Dimensional Microbiome Data .pad-left[ - Descriptive: - heatmaps - stacked barplots - Test a priori hypotheses regarding specific OTUs/taxa. - Reduce dimensions: - single summary statistic (alpha diversity) - pairwise distances (beta diversity) with PCoA or PERMANOVA - community types (mixture modeling) ] --- class: top left background-image: url(img/pptx_img/image4.png) background-size: contain --- class: top left background-image: url(img/pptx_img/image3.png) background-size: contain --- ## Descriptive: Heatmaps & Barplots .pad-left[ - Visualization of OTU table: - typically present counts as a proportion of sample total - choice of sample order can highlight group differences - Limitations: - cannot depict full list of OTUs - space dictates taxonomic level presented ] --- ## Single-Taxon hypotheses .pad-left[ - You suspect Bacteroides has a relationship with outcome of interest... - Bacteroides (genus)? - Bacteroidaceae (family)? - Bacteroidales (order)? - Bacteroidetes (class)? - functional group (e.g., butyrate production)? - Hypotheses focusing on specific taxa often fail to account for **possibility of selection bias from culture**. ] ---
OTU
phylum
class
order
family
genus
OTU_97.1
Firmicutes
Bacilli
Lactobacillales
Lactobacillaceae
Lactobacillus
OTU_97.10
Firmicutes
Clostridia
Clostridiales
Veillonellaceae
Veillonella
OTU_97.100
Firmicutes
Clostridia
Clostridiales
Veillonellaceae
NA
OTU_97.1000
Proteobacteria
Betaproteobacteria
NA
NA
NA
OTU_97.10000
Actinobacteria
Actinobacteria
Actinomycetales
Propionibacteriaceae
Propionibacterium
OTU_97.10001
Firmicutes
Bacilli
Lactobacillales
Lactobacillaceae
Lactobacillus
OTU_97.10002
Firmicutes
Clostridia
Clostridiales
Lachnospiraceae
NA
OTU_97.10003
Actinobacteria
Actinobacteria
Actinomycetales
Propionibacteriaceae
Propionibacterium
OTU_97.10004
Actinobacteria
Actinobacteria
Actinomycetales
Corynebacteriaceae
Corynebacterium
OTU_97.10005
Bacteroidetes
Bacteroidia
Bacteroidales
Bacteroidaceae
Bacteroides
--- ## Dimension Reduction: Alpha Diversity .pad-left[ - Summarize each sample’s community in a single measure: - richness: number of community members - evenness: the distribution of member counts - Many alpha diversity metrics (weight richness/evenness): - species number, Chao1 (singletons & doubletons) - Shannon diversity: `\(H' = - \sum_{i} p_{i} \cdot \log(p_{i})\)` (note: may measure similarity or dissimilarity) ] --- class: top left background-image: url(img/pptx_img/image2.png) background-size: contain --- ## Dimension Reduction: Beta Diversity .pad-left[ - Summarize each sample’s relationship to other samples: - pairwise distances - OTU table → square matrix - Many beta diversity metrics: - just counts versus counts + phylogeny - weighted versus unweighted - (Euclidean versus non-Euclidean) ] --- class: top left background-image: url(img/pptx_img/image19.png) background-size: contain .footnote-right[Anderson MJ et al. _Austral Ecol_ 2001;26(1):32-46.] --- --- class: top left hide-count background-image: url(img/christina-victoria-craft-WHSnkIwWpec-unsplash.jpeg) background-size: cover ## <span style='color: #226252'>The LBP Era</span> .footnote-right[<span style='color: white'>photo: Christina Victoria Craft @unsplash</span>] --- class: middle right hide-count background-image: url(img/Gemini_Generated_Image_i7lg9vi7lg9vi7lg_crop.jpg) background-size: cover ## <span style='color: white;'>Future Considerations</span> .footnote-left[<span style='color: white'>photo: Google Gemini</span>] --- ## MBT Efficacy Beyond R-CDI & Beyond the Gut .pull-left[ <img src="img/otto_bacillus_effect.png" width="100%" style="display: block; margin: auto;" /> ] .pull-right[ - MDRO pathogen burden reduction: - FMT reduces gut reservoir of MDROs by strain replacement - MRSA decolonization: - oral probiotic _B. subtilis_ MB40 reduces not just enteric but also nasal reservoirs of MRSA ] .footnote-left[Gopalsamy et al _ICHE_ 2018; Saha et al _CMI_ 2019; Woodworth et al _STM_ 2023; Piewngam et al _Lancet Microbe_ 2023] --- ## Acknowledgements .pull-left[ - __MOTION Lab & C-STAR @ Penn__ Laura Cowden, Laurel Glaser, Kyle Rodino, Sean Loughrey, Magda Wernovsky, Erik Clarke, Michael David, Matt Ziegler, Lauren Dutcher, Ebbing Lautenbach, Jim Harrigan, Alexa Patel, Dylan Tapper, Anne Jaskowiak, Pam Tolomeo - __Bushman Laboratory @ Penn__ Arwa Abbas, Aoife Roche, Andrew Marques, Aubrey Bailey, John Everett, Rick Bushman - __PennCHOP Microbiome Program__ Lisa Mattei, Huanjia Zhang, Kyle Bittinger ] .pull-right[ - __Collman Laboratory @ Penn__ Ize Imai, Aurea Simon Soro, John McGinniss, Ron Collman - __Division of ID @ Penn__ Ian Frank, Pablo Tebas, Robert Gross, Emily Blumberg - __Rutgers University & Penn DBEI__ Jason Roy, Arman Oganisian - __AGA FMT National Registry__ Gary Wu, Colleen Kelly, Jim Lewis - __Funding__ <u>CDC</u>: BAAs 200-2016-91964, 200-2018-02919, 200-2021-10986 & <u>NIAID</u>: K23 AI121485, U19AI174998 ] .center[ ## brendank@upenn.edu ] --- class: bottom center hide-count background-image: url(img/adrian-lange-Wk902ZLaA7M-unsplash_crop.jpg) background-size: cover .title-text[<span style='font-size:0.5em; color:#ffffff'>Questions?</span>] .footnote-right[<span style='color:#ffffff'>photo: Adrian Lange @unsplash</span>]